Cardiac Glycosides

Digitalis

Dr. Ragaa Darwish

Prof. Forensic
Medicine &Toxicology
 Learning Objectives
1. Define the nature of digitalis
2. Identify sources & modes of exposure
3.List the indications for digoxin use.
4. Recognize the pathophysiology of DT
5. Identify the physical S & S of toxicity.
6. Describe initial management of digitalis
toxicity.
What is a cardiac
glycoside ?
It is a naturally occurring drug whose action
includes both beneficial and toxic effects
on the heart. Cardiac Glycosides are
composed of two structural features :
-the sugar (glycone) moiety
+
-the non-sugar (aglycone) m.
Cardiac Glycosides:
Digitalis purpura,lanata
Oleander

Lily of valley
 Medications

 The most common cardiac glycoside

medication is : Digoxin
from digitalis purpura
 Other active principles:

Digitoxin
from digitalis lanata
 Digitalis Glycosides in Clinical Use

Digoxin Digitoxin
Lipid Solubility Medium High
Oral Absorption 75% >90%
Plasma Binding 20-40% >90%
Half Life 1.6 days 7 days
Route of Elimination Kidney Liver
 What are the beneficial cardiac
effects of digoxin?
 Uses: 1- Cardiac tonic in HF
Uses: 2- Antiarrhytmic :
Atrial Flutter, Atrial
Fibrillation
Atrial flutter
Atrial fibrillation
 In a therapeutic dosage,
the effects of digoxin
include:
• Increased myocardial contractility

• Decreased AV conduction rate

• Decreased heart rate

Digoxin has the narrowest
therapeutic range of any
commonly used medication
Circumstances of Digoxin
Toxicity...
Chronic Toxicity:
Patients who are taking digoxin
therapeutically.

Acute Toxicity:
Patients who have taken an overdose:
- deliberatly
- accidentally
- ingested a plant
containing card. glycosides
 How medicines are handled by
the body
Liver

Gut Blood METABOLISM

wall

ABSORPTION DISTRIBUTION Kidney

ELIMINATION
Role Preparation For NAs: Handling Medicines Calls
PHARMACODYNAMICS

Absorption: GIT.
 
Metabolism: Liver.

Excretion: -Renal (mainly),

Rexcretion: -Enterohepatic circulation

in bile (small).
 Diagram of first pass effect
biliary tract
metabolised drug

liver

portal vein
gut
to circulation unmetabolised
drug
 Diagram of entero-hepatic
circulation
conjugated drug
biliary tract

liver
bacteria
portal vein
unconjugated
drug gut
to circulation
MECHANISM OF ACTION:

Inhibits Na+-K+ ATPase in

cell membranes,
and Interfere with Na+-K+
Pump
Active Transport: Na-K Pump -
Step 1

 Three sodium ions from inside the

cell first bind to the transport protein.
Active Transport: Na-K Pump -
Step 2

Then a phosphate group is transferred from

ATP to the transport protein causing it to
change shape and release the sodium ions
outside the cell.
 Active Transport: Na-K Pump -
Step 3

 Then a phosphate group is transferred from

ATP to the transport protein causing it to
change shape and release the sodium ions
outside the cell.
Active Transport: Na-K Pump -
Step 4

 Two potassium ions from outside the

cell then bind to the transport
protein.
 Active Transport: Na-K Pump -
Step 5
* High conc.
of Na+ outside the cell

* High conc
of K+ inside the cell

 As the phosphate is removed, the protein

assumes its original shape and releases the
potassium ions inside the cell.
 MECHANISM OF ACTION:

 The end result (intracellularly) is

sodium
calcium
 ACTION
+ve Inotropic effect (Contraction):
Increases Contractility → ↑ COP (Na+-
K+Pump)

-ve Chromotropic Effect (Rate):

Increases Vagal Tone → ↓ Heart Rate
-ve Dromotropic Effect
(Conduction): *Depresses Conduction
Velocity of the heart
(Slows AV node conduction )
What are the "normal" ECG
changes with digoxin?
 Prolonged PR interval
 Shortened QT interval

 ST segment depression

 Inverted T wave
 Digitalis toxicity
The usual effects of digoxin are amplified
 ↑Excitability →ectopic beats
↑Automaticity → tachyarrythmias
 ↓ Heart Rate →the heart rate slows further.
 ↓ conduction (through AV) →
further slows → Sinus bradycardia

→ AV block
 Predisposing Factors to
Toxicity
 Patient : old, renal failure, hepatic dysfunction.
Patient : old, renal failure, hepatic dysfunction.
 Electrolyte abnormalities
↓ K+ ↓ Mg++ ↑Na+ ↑Ca++
 Drug interactions
Antibiotics: erythromycins, tetracyclines
They destroy gut flora that normally metabolize
digoxin before it is absorbed→↑serum digoxin
Quinidine: competes with digoxin for myocardial
receptor sites→displaces dig from bind
K-depleting diuretics
Calcium
DIGOXIN TOXICITY TOXIDROME
Asymptomatic period: min - hrs
GIT: Anorexia, nausea, vomiting, cramps.
CNS: -Altered mental status:
(disorientation, confusion, drowziness, lethargy)
-Headache, diziness, fatigue, weakness,
-hallucinations, agitations, seizures (very rare).

Occular: Blurred vision, photophobia,

abnormal color perception, toxic amblyopia,
xanthopsia (seeing yellow-green halos).
 Occular:
Visual disturbances are probably the hallmark
of digitalis toxicity.
 blurred or double vision
 sensitivity to light (photophobia)
 toxic amblyopia
 color vision disturbances where things start to
look green or yellow
 vision of a yellow "halo" around lights or
xanthopsia (blind spots)
Toxidrome cont.

Cardiovascular:
 CHF exacerbation

 Slow full pulse,

 Hypotension, shock, asystole

 All types of arrhythmias.

 There are many types of
arrythmias:
excitant,

Suppres
sant
Combin
ed.
 Suppressant:
Sinus Bradycardia, SA Block, AV Block

Excitant:
PVCs, VT, V Fib
AT, A Fl, A Fib

Combined:
Atrial Tachycardia +Atrial-ventricular Block
 ACUTE CHRONIC
Age Young Elderly
Intention Intentional Accidental
GI N,V, anorexia , D, Less
abd pain
CNS Less Headache , fatigue ,
weakness, dizziness,
confusion ,visual,coma

Electrolyte/ Hyperkalaemia, Hypokalemia, Normal

Renal normal renal Renal insufficiency
function
Cardiac Bradyarrhythmia, Ventricular dysrhythmia
SVT
 Management
Diagnosis
 Circumstantial evidence.
 History → Cardiac medication

 Clinical Picture

 ECG → Combination of excitant+ suppressant

(Diagnostic) e.g. Sinus tachycardia+ Block
Prolonged P-R +depressed S-
T

 Laboratory
 Laboratory
 Glucose determination
 Complete Blood Count

 Serum Potassium

 Serum Magnesium and Calcium

 Serum BUN and Creatinine

 Serum Digoxin
Serum Potassium
Hyperkalemia: ↑ K
Seen in Acute toxicity
correlates better than dig serum level.
if serum K > 5.5 meq/L prognosis poor
 
Hypokalemia: ↓ K
Common in Chronic toxicity
Patients taking diuretics
Contributes more to digoxin toxicity
 Serum Digoxin
*Therapeutic serum level: 0.6 - 2.0 ng/ml.
About 2/3of people will experience
symptoms of toxicity at a blood level
over 2.0 ng/mL.
* Digoxin needs betw 6 and 8 hours to
distribute itself within the body, so a
level that is drawn < 6 hours after
ingestion may give an extremely high
value that does not mean toxicity .
  * Elevated levels of digoxin only confirm
exposure
 Serum Digoxin

* Assessed by digoxin
radioimmunoassays
(RIAs) .
 TREATMENT
 Stop the drug,
 ABCs,
 D: GID to prevent absorption:
-Gastric lavage, avoid emesis
-Activated charcoal, repeated
-Cholestyramine (steroid-binding
resin) 15-30gm oral /3-4 dd
 DONT regimen for altered mental status,
 TREATMENT
 Correct K disturbance,
Hyperkalemia: Insulin 20 units in
5% dextrose
Calcium is contraindicated to
treat hyperkalemia because
ventricular tachyc fibrill may be
precipit.
Hypokalemia: K replacement to
achieve >4mq
 Replete Mg, with IV magnesium
sulfate
  Management of cardiac arrythmias

 Monitoring
 NB Patients with rhythm
disturbances are to be monitored
in ICU
 Treatment of arrythmias:
 Bradycardia: Early cases, Atropine 1-2 mg IV,
Persistent cases, Pacemaker.

 Ventricular arrythmias:
Phenytoin: -Drug of choice -Action at AV node
-beneficial in AT + AV Block
- dose 0.5 mg/kg slowly IV at 1-2hrs interval

Lidocaine: - for ventricular tachycardia

Mg SO4: -Consider
- magnesium therapy. It may be
lifesaving
 Quinidine: Contraindicated.
  Physiological
antidote:Digibind
Digoxin Specific Antibody
Fab: Fragmented Anti Body

Binds to free Digoxin

obilizes Dig. from tissue binding sites

purified from sheep

 Fab Fragments + Digoxin

Fab Fragments Digoxin Complex

excreted in the urine.
Digoxin Specific Antibody Fab
Fragments
Indications: -Life-threatening VT and V Fib,
-Progressive Bradycardia
-Hyperkalemia Serum K>5.5
meq/L

 For an acute overdose in adults:

 Give 10 vials IV & repeat if indicated

 With chronic toxicity:

 Give 2 vials to an adult

 One vial of digibind contains 40 mg, which neutralizes

approximately 0.5 mg of digoxin
 How long does it take for
the Digibind to work?

The average onset of action for

Digibind is

30 minutes . 
 90 minutes showed complete
recession of all toxicity symptoms,
including ECG changes.
What about hemodialysis or
hemoperfusion?
Digoxin is not cleared by either
hemodialysis or hemoperfusion
because of
 the drug’s large volume of
distribution and its molecular weight
  Hemodialysis may be initiated for
renal failure, but is not effective as a
treatment for the overdose